Novel pyrazoline derivatives as bi-inhibitor of COX-2 and B-Raf in treating cervical carcinoma

Bioorg Med Chem. 2014 Aug 1;22(15):4109-18. doi: 10.1016/j.bmc.2014.05.059.

Minmin Yu ¹, Hui Yang ², Kaihua Wu ³, Ying Ji ³, Lili Ju ³, Xiaoyuan Lu ⁴

Affiliations

1 Department of Obstetrics and Gynecology, Second Affiliated Hospital of Southeast University, Nanjing 210003, China. Electronic address: yuminmin324@126.com.
2 Department of Obstetrics and Gynecology, Huai'an Maternal and Child Health Hospital, 223002, China.
3 Department of Obstetrics and Gynecology, Second Affiliated Hospital of Southeast University, Nanjing 210003, China.
4 Department of Obstetrics and Gynecology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221006, China. Electronic address: xy_lu68@aliyun126.com.

PMID: 24934992 DOI: 10.1016/j.bmc.2014.05.059

Abstract

Twenty four pyrazoline derivatives modified from Celecoxib were designed and synthesized as bi-inhibitor of COX-2 and B-Raf. They were evaluated for their COX-1/COX-2/B-Raf inhibitory and anti-proliferation activities. Compound A3 displayed the most potent activity against COX-2 and HeLa cell line (IC₅₀=0.008 μM; GI₅₀=19.86 μM) and showed superb COX-1/COX-2 selectivity (>500), being more potent and selective than positive control Celecoxib or 5-fluorouracil. Compounds A5 and B5 were introduced best B-Raf inhibitory activities (IC₅₀=0.15 μM and 0.12 μM, respectively). Compound A4 retained superb bioactivity against COX-2 and HeLa cell line (IC₅₀=0.015 μM; GI₅₀=23.82 μM) and displayed moderate B-Raf inhibitory activity (IC₅₀=3.84 μM). Docking simulation was conducted to give binding patterns. QSAR models were built using bioactivity data and optimized conformations to provide a future modification of COX-2/B-Raf inhibitors.

Keywords

3D QSAR; B-Raf; Bi-inhibitor; COX-2; Celecoxib; Cervical carcinoma; Modification; Pyrazoline.

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